Characterization of a Novel Hepatitis C Subtype, 6xj, and Its Consequences for Direct-Acting Antiviral Treatment in Yunnan, China

Jia, Yuanyuan; Yue, Wei; Gao, Qinghua; Tao, Rui; Zhang, Yaxiang; Fu, Xiouhua; Liu, Yang; Liu, Li; Feng, Yue; Xia, Xueshan

doi:10.1128/spectrum.00297-21

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…Notably, it is highly prevalent in Southern China and Southeast Asia, including Laos, Vietnam, and Cambodia where the infection rates range from 27% to 95% 6,7 . GT6 exhibits the highest genetic diversity within HCV GTs, as assessed by intra‐GT pairwise distance, and has been divided into at least 32 subtypes (a to xj) 8 …”

Section: Introductionmentioning

confidence: 99%

“…6,7 GT6 exhibits the highest genetic diversity within HCV GTs, as assessed by intra-GT pairwise distance, and has been divided into at least 32 subtypes (a to xj). 8 There are three types of anti-HCV DAAs according to their antiviral targets: NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors. 9 Although current interferon(IFN)-free oral regimens are potent and convenient, the natural presence of resistance-associated variants (RAV) and the emergence of resistanceassociated substitutions (RAS) during the DAA treatment can lead to therapy failure.…”

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confidence: 99%

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Construction and characterization of a new hepatitis C virus genotype 6a subgenomic replicon that is prone to render the sofosbuvir resistance

Liu,

Guo,

Han

et al. 2023

Journal of Medical Virology

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Hepatitis C virus (HCV) infection remains a challenge to human public health despite the development of highly effective direct‐acting antivirals (DAAs). Sofosbuvir (SOF), a key component in most DAA‐based anti‐HCV cocktail regimens, is a potent viral RNA polymerase (NS5B) inhibitor with a high barrier to drug resistance. The serine‐to‐threonine mutation at NS5B 282 (S282T) confers the SOF resistance, but severely impairs viral replication in most HCV genotypes (GTs) and cannot be stably maintained after the termination of the SOF‐based therapies. In this study, we first developed a new HCV GT‐6a subgenomic replicon PR58D6. Next, we selected SOF‐resistant PR58D6 variants by culturing the replicon cells in the presence of SOF. Interestingly, unlike many other HCV replicons which require additional mutations to compensate for the S282T‐inducing fitness loss, S282T alone in PR58D6 is genetically stable and confers the SOF resistance without significantly impairing viral replication. Furthermore, we showed that amino acid residue at NS5B 74 (R74) and 556 (D556) which are conserved in GT 6a HCV contribute to efficient replication of PR58D6 containing S282T. Finally, we showed that the G556D mutation in NS5B could rescue the replication deficiency of the S282T in JFH1, a GT‐2a replicon. In conclusion, we showed that a novel GT‐6a HCV replicon may easily render SOF resistance, which may call for attention to potential drug resistance during DAA therapies of HCV GT‐6a patients.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Construction and characterization of a new hepatitis C virus genotype 6a subgenomic replicon that is prone to render the sofosbuvir resistance

Liu,

Guo,

Han

et al. 2023

Journal of Medical Virology

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“…HCV is a single-stranded, positive-sense RNA virus, with a genome of ~9.6 kb in length that encodes a single open reading frame (ORF) flanked by 5′ and 3′ untranslated regions (UTRs). Modern genetic diversity and phylogenetic analyses indicate that the virus is classifiable into eight major genotypes (GTs) and 92 distinct subtypes ( Jia et al., 2021 ). Different HCV GTs have distinct geographical distributions and differ in their responses to antiviral therapies.…”

Section: Introductionmentioning

confidence: 99%

The distribution of hepatitis C viral genotypes shifted among chronic hepatitis C patients in Yunnan, China, between 2008–2018

Jia

Zou

Yue

et al. 2023

Front. Cell. Infect. Microbiol.

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ObjectThe hepatitis C virus (HCV) is prevalent across China, with a distinctive genotypic distribution that varies by geographical region and mode of transmission. Yunnan is one such geographical region wherein the local population continues to experience a high level of HCV infection, severely straining public health resources. This high prevalence is likely due to the increased incidence of intravenous drug use in that region, as Yunnan is a major point of entry for illegal heroin into China.MethodsWe investigated 510 individuals with chronic HCV infections in Yunnan Province from 2008 through 2018. Using reverse transcription PCR and Sanger sequencing to amplify and sequence samples. Bayesian analyses was performed to estimate the common ancestors and Bayesian skyline plot to estimate the effective viral population size. Molecular network was conducted to explore the characteristics of HCV transmission.ResultsWe successfully amplified and sequenced a total of 503 viral samples and genotyped each as either 3b (37.6%), 3a (21.9%), 1b (19.3%), 2a (10.5%), HCV-6 (10.1%), or 1a (0.6%). Over this 11-year period, we observed that the proportion of 3a and 3b subtypes markedly increased and, concomitantly, that the proportion of 1b and 2a subtypes decreased. We also performed Bayesian analyses to estimate the common ancestors of the four major subtypes, 1b, 2a, 3a, and 3b. Finally, we determined that our Bayesian skyline plot and transmission network data correlated well with the changes we observed in the proportions of HCV subtypes over time.ConclusionsTaken together, our results indicate that the prevalence of HCV 3a and 3b subtypes is rapidly increasing in Yunnan, thus demonstrating a steadily growing public health requirement to implement more stringent preventative and therapeutic measures to curb the spread of the virus.

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“…A study by Jia et al identified a new HCV GT6 subtype, 6xj, and baseline RAS associated with it. They demonstrated that 28V and 32L substitutions did not affect attainment of sustained biological responses [ 10 ]. In addition, literature regarding genetic diversity within HCV GT6, its epidemiological manifestations, and prevalence of RASs is still insufficient.…”

Section: Introductionmentioning

confidence: 99%

Treatment Response and Drug Resistance Profiling of Genotype 6 of Hepatitis C Virus in HCV/HIV Co-Infected Patients: A Pilot Study from INDIA

Gupta

Samal

Pandey

et al. 2022

Viruses

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Hepatitis C Virus (HCV) genotype (GT) 6 demonstrates maximum genomic diversity out of all the known genotypes of HCV, attributable to its inherent intra-genotype and inter-genotype recombination property. This is the most common genotype seen in HCV/HIV co-infected cases. HIV/HCV co-infection is linked with increased genetic diversity in HCV structural genes. The detailed information on the distribution of HCV GT6, its subtypes, and resistance to currently available antiviral drugs is limited in the Indian subcontinent. Therefore, in this single-center retrospective cross-sectional study, we aimed to map the occurrence of HCV GT6, its subtypes and resistance-associated substitution (RAS), and its correlation with antiviral treatment response in HCV-infected patients. From a cohort of 2052 HCV-infected patients, the overall prevalence of GT6 was 2.5% (n = 53), with a maximum of 81.1% (n = 43) seen in HCV/HIV co-infected patients. Nine different subtypes, 6a, 6b, 6f, 6i, 6n, 6u, 6v, 6w, and 6xa, were detected in the Indian population for the first time, with a predominance of 6xa (41.5%), a rare subtype, followed by 6n (39.6%). The phylogenetic analysis by the neighbor-joining method revealed three prominent viral clades, 6v, 6n, and 6xa–6u. The baseline (before treatment initiation) plasma samples of all GT6-infected patients were retrieved from −80 °C and a part of the NS5a and NS5b region of the viral genome was analyzed for the presence of RAS. No RASs were seen in the NS5b region, while in two patients (3.7%) RASs were seen at baseline in the NS5a region of the virus. Sustained viral response (SVR) was attained in 81% (n = 43) of patients. No difference in GT6 subtype distribution or occurrence of RAS was seen between mono-infected HCV and HIV/HCV co-infected cases. Our study revealed that RAS at baseline did not influence the attainment of SVR and the currently available antiviral therapy is effective against GT6 mono-infected and HIV/HCV co-infected patients.

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Characterization of a Novel Hepatitis C Subtype, 6xj, and Its Consequences for Direct-Acting Antiviral Treatment in Yunnan, China

Abstract: This study investigated the genetic diversity of hepatitis C virus (HCV), particularly in relation to genotype 6, which is prevalent in Yunnan, China, and is often difficult to treat successfully. We identified a new HCV-6 subtype, 6xj, which is an ancient strain.

Cited by 7 publications

References 26 publications

Construction and characterization of a new hepatitis C virus genotype 6a subgenomic replicon that is prone to render the sofosbuvir resistance

Construction and characterization of a new hepatitis C virus genotype 6a subgenomic replicon that is prone to render the sofosbuvir resistance

The distribution of hepatitis C viral genotypes shifted among chronic hepatitis C patients in Yunnan, China, between 2008–2018

Treatment Response and Drug Resistance Profiling of Genotype 6 of Hepatitis C Virus in HCV/HIV Co-Infected Patients: A Pilot Study from INDIA

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